| 1. |
- Kanai, M, et al.
(author)
-
- 2023
-
swepub:Mat__t
|
|
| 2. |
- Niemi, MEK, et al.
(author)
-
- 2021
-
swepub:Mat__t
|
|
| 3. |
- Benatar, Michael, et al.
(author)
-
Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
-
In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
-
Journal article (peer-reviewed)abstract
- Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
|
|
| 4. |
- Bornemann, Till L., V, et al.
(author)
-
Genetic diversity in terrestrial subsurface ecosystems impacted by geological degassing
- 2022
-
In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 13:1
-
Journal article (peer-reviewed)abstract
- Earth's mantle releases 38.7 +/- 2.9 Tg/yr CO2 along with other reduced and oxidized gases to the atmosphere shaping microbial metabolism at volcanic sites across the globe, yet little is known about its impact on microbial life under non-thermal conditions. Here, we perform comparative metagenomics coupled to geochemical measurements of deep subsurface fluids from a cold-water geyser driven by mantle degassing. Key organisms belonging to uncultivated Candidatus Altiarchaeum show a global biogeographic pattern and site-specific adaptations shaped by gene loss and inter-kingdom horizontal gene transfer. Comparison of the geyser community to 16 other publicly available deep subsurface sites demonstrate a conservation of chemolithoautotrophic metabolism across sites. In silico replication measures suggest a linear relationship of bacterial replication with ecosystems depth with the exception of impacted sites, which show near surface characteristics. Our results suggest that subsurface ecosystems affected by geological degassing are hotspots for microbial life in the deep biosphere. Geological degassing can impact subsurface metabolism. Here, the authors describe microbial communities from a cold-water geyser are described and compared with other deep subsurface sites, finding a key role for an uncultivated archaeon.
|
|
| 5. |
- Gergei, Ingrid, et al.
(author)
-
GWAS META-analysis followed by MENDELIAN randomisation revealed potential control mechanisms for circulating α-klotho levels.
- 2022
-
In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 31:5, s. 792-802
-
Journal article (peer-reviewed)abstract
- The protein α-Klotho acts as transmembrane the co-receptor for fibroblast growth factor 23 (FGF-23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a GWAS meta-analysis followed by Mendelian randomisation (MR) of circulating α-Klotho levels.Plasma α-Klotho levels were measured by ELISA in the LURIC and ALSPAC (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts.Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (p<5×10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained >9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF-23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes, followed by targeted MR suggested causal effects of liability of Crohn's disease risk [IVW beta=0.059 (95% CI 0.026, 0.093)] and low-density lipoprotein cholesterol (LDL-C) levels [-0.198, (-0.332, -0.063)] on α-Klotho.Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively.
|
|
| 6. |
- Hagsand, Angelica, 1985, et al.
(author)
-
A survey of police officers encounters with sober, alcohol- and drug-intoxicated suspects in Sweden
- 2022
-
In: Psychology, Crime and Law. - 1068-316X. ; 28:5, s. 523-544
-
Journal article (peer-reviewed)abstract
- Alcohol-related crimes are very common globally, including in Scandinavia. Despite this, no survey to date has examined the prevalence of alcohol- and drug-intoxicated suspects in Sweden specifically, or which procedures police use when interacting with this suspect group. Given the current lack of (inter)national policy guidelines on how to interrogate intoxicated persons, it is important to examine law enforcement’s contact with this potentially vulnerable group in different contexts. This was the aim of the present study. Data were collected via an online survey sent out to Swedish police investigators and 133 officers responded in total. A large majority (87%) of responses indicated that it was common or very common to encounter intoxicated suspects, but findings also suggest that police departments differ in their procedures for when and how to conduct investigations and interviews involving drunk suspects. Our findings support the need for (inter)national guidelines on how to interview intoxicated suspects and the need for more scientific studies on how alcohol affects suspect’s memory and decision making.
|
|
| 7. |
- Hagsand, Angelica, 1985, et al.
(author)
-
Police survey: Procedures and prevalence of intoxicated witnesses and victims in Sweden.
- 2022
-
In: The European Journal of Psychology Applied to Legal Context. - 1889-1861 .- 1989-4007. ; 14:1, s. 11-21
-
Journal article (peer-reviewed)abstract
- Background: Despite the common occurrence of alcohol-related crimes, the Swedish police authority currently lacks national guidelines for dealing with intoxicated victims/witnesses. Method: A survey was designed to explore the police procedures when encountering intoxicated individuals and to compare the findings with international statistics. To facilitate international comparison, the survey was modeled after previous research and adapted to a Swedish context. A solicitation containing a link to the survey was emailed to all police regions in Sweden. Results: Police officers (N = 133) indicated that it was common to interact with intoxicated witnesses/victims. Some police departments had local guidelines on how to conduct investigative interviews with intoxicated individuals, but it was mostly up to each officer to make a subjective judgement regarding interactions with this witness group. Data evidenced that the high prevalence rate of intoxicated witnesses/victims in Sweden is similar to rates in Australia, the U.S. and U.K. It appears that the Swedish police are unaware of research concerning when and how to conduct investigative interviews with intoxicated witnesses and victims, a potentially vulnerable group. Conclusions: A closer collaboration between police and researchers is encouraged in order to develop guidelines for investigations with intoxicated individuals.
|
|
| 8. |
- Juzenas, Simonas, et al.
(author)
-
Detailed transcriptional landscape of peripheral blood points to increased neutrophil activation in treatment-naïve inflammatory bowel disease
- 2022
-
In: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 16:7, s. 1097-1109
-
Journal article (peer-reviewed)abstract
- BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn's disease (CD) or ulcerative colitis (UC). These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and thus, common immune regulatory pathways.METHODS: Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve (n=110) and treatment-exposed (n=177) IBD patients as well as symptomatic- (n=65) and healthy controls (n=95).RESULTS: Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, the IL1B was identified as the central gene. The co-expression levels among IL1B and chemosensing receptor (CXCR1/2 and FPR1/2) genes were reduced in the blood of IBD patients when compared with healthy controls.CONCLUSIONS: Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation.
|
|
| 9. |
- Pettersson, Daniel, et al.
(author)
-
Face recognition performance among alcohol-intoxicated witnesses in the field.
- 2020
-
In: Oral presentation at the 1th virtual conference of the European Association of Psychology and Law (EAPL)..
-
Conference paper (other academic/artistic)abstract
- Background: The aim of the present study was to further investigate prior research’s inconsistent results on how alcohol-intoxication affects eyewitness face identification ability in field settings, including moderately and highly intoxicated witnesses. As data collection is ongoing, the present submission is based on a preliminary data set. Method: Volunteer bar patrons (N = 68) first viewed a mock-crime video and were then asked to identify the perpetrator from either a target-present or target-absent photo show-up. Breath alcohol content (BrAC) was measured with a portable breathalyzer and ranged from 0.00-0.15% (M = .05%, SD = .04). Result: Relationships between identification accuracy and BrAC levels were analyzed using a logistic regression with BrAC, show-up condition (target-present vs. target-absent) and the interaction as predictors; and identification accuracy (correct vs. incorrect) as outcome. Analyses revealed that neither BrAC level nor the interaction had a significant influence on identification accuracy. However, show-up condition did, β = 2.12, SE = .58, Wald (1) = 13.49, p < .001, OR = 8.33, 95% CI [2.69, 25.84]. Regardless of intoxication level, participants had an easier time making a correct decision (83% rejections) when the photo showed the innocent look alike in the target-absent condition. This is in contrast to a smaller portion of correct decisions in the target-present condition, where only 37% of the witnesses correctly identified the real perpetrator. Conclusions: Similar to prior research (e.g., Altman et al., 2018) our preliminary findings suggest that face recognition may be robust against alcohol-intoxication. As data collection continues, we expect to collect more data from highly intoxicated participants in the field to reassess these findings at higher BrAC levels, yielding direct implications for legal settings and public policy.
|
|
| 10. |
- Swift, Imogen J, et al.
(author)
-
A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.
- 2024
-
In: Alzheimer's Research & Therapy. - 1758-9193. ; 16:1
-
Journal article (peer-reviewed)abstract
- Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p=0.007) with a trend in non-carriers (p=0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
|
|
